SummaryIn most European countries social insurance programs, like welfare, unemployment insurance and disability insurance are characterized by low reemployment rates. Therefore, governments spend huge amounts of money on active labour market programs, which should help individuals in finding work. Recent surveys indicate that programs which aim at intensifying job search behaviour are much more effective than schooling programs for improving human capital. A second conclusion from these surveys is that despite the size of the spendings on these programs, evidence on its effectiveness is limited. This research proposal aims at developing an economic framework that will be used to evaluate the effectiveness of popular programs like offering reemployment bonuses, fraud detection, workfare and job search monitoring. The main innovation is that I will combine economic theory with recently developed econometric techniques and detailed administrative data sets, which have not been explored before. While most of the literature only focuses on short-term outcomes, the available data allow me to also consider the long-term effectiveness of programs. The key advantage of an economic model is that I can compare the effectiveness of the different programs, consider modifications of programs and combinations of programs. Furthermore, using an economic model I can construct profiling measures to improve the targeting of programs to subsamples of the population. This is particularly relevant if the effectiveness of programs differs between individuals or depends on the moment in time the program is offered. Therefore, the results from this research will not only be of scientific interest, but will also be of great value to policymakers.

In most European countries social insurance programs, like welfare, unemployment insurance and disability insurance are characterized by low reemployment rates. Therefore, governments spend huge amounts of money on active labour market programs, which should help individuals in finding work. Recent surveys indicate that programs which aim at intensifying job search behaviour are much more effective than schooling programs for improving human capital. A second conclusion from these surveys is that despite the size of the spendings on these programs, evidence on its effectiveness is limited. This research proposal aims at developing an economic framework that will be used to evaluate the effectiveness of popular programs like offering reemployment bonuses, fraud detection, workfare and job search monitoring. The main innovation is that I will combine economic theory with recently developed econometric techniques and detailed administrative data sets, which have not been explored before. While most of the literature only focuses on short-term outcomes, the available data allow me to also consider the long-term effectiveness of programs. The key advantage of an economic model is that I can compare the effectiveness of the different programs, consider modifications of programs and combinations of programs. Furthermore, using an economic model I can construct profiling measures to improve the targeting of programs to subsamples of the population. This is particularly relevant if the effectiveness of programs differs between individuals or depends on the moment in time the program is offered. Therefore, the results from this research will not only be of scientific interest, but will also be of great value to policymakers.

SummaryAtherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVD), is a lipid driven, inflammatory disease of the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of atherosclerosis-induced CVD risk remains unaddressed. Therefore, characterizing mediators of the inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications.
Co-stimulatory molecules are key players in modulating immune interactions. My laboratory has defined the co-stimulatory CD40-CD40L dyad as a major driver of atherosclerosis. Inhibition of CD40, and of its interaction with the adaptor molecule TRAF6 by genetic deficiency, antibody treatment or (nanoparticle based) small molecule inhibitor (SMI) treatment, is one of the most powerful therapies to reduce atherosclerosis in a laboratory setting. Although CD40-CD40L interactions are associated with adaptive immunity, I recently identified the macrophage as a driver of CD40-induced inflammation in atherosclerosis. We will use state-of-the-art in vitro experiments, live cell-, super resolution imaging, proteomics approaches and mutant mouse models to unravel the role of macrophage CD40 in atherosclerosis. Moreover, using structure based virtual ligand screening, I will develop lead SMIs targeting macrophage CD40-signaling, which I will deliver using macrophage-targeting nanoparticles. My goal is to define the role of macrophage CD40 in inflammation and immunity and disentangle how its activation affects atherosclerosis. I will finally test the feasibility of targeting macrophage CD40-signaling as a treatment for CVD.
These studies will define the role of CD40-signaling in the innate immune system in health and (cardiovascular) disease. As components of macrophage CD40-signaling have the potential to be amenable to pharmacological manipulation, we will establish their feasibility as novel targets for (CVD) treatment.

Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVD), is a lipid driven, inflammatory disease of the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of atherosclerosis-induced CVD risk remains unaddressed. Therefore, characterizing mediators of the inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications.
Co-stimulatory molecules are key players in modulating immune interactions. My laboratory has defined the co-stimulatory CD40-CD40L dyad as a major driver of atherosclerosis. Inhibition of CD40, and of its interaction with the adaptor molecule TRAF6 by genetic deficiency, antibody treatment or (nanoparticle based) small molecule inhibitor (SMI) treatment, is one of the most powerful therapies to reduce atherosclerosis in a laboratory setting. Although CD40-CD40L interactions are associated with adaptive immunity, I recently identified the macrophage as a driver of CD40-induced inflammation in atherosclerosis. We will use state-of-the-art in vitro experiments, live cell-, super resolution imaging, proteomics approaches and mutant mouse models to unravel the role of macrophage CD40 in atherosclerosis. Moreover, using structure based virtual ligand screening, I will develop lead SMIs targeting macrophage CD40-signaling, which I will deliver using macrophage-targeting nanoparticles. My goal is to define the role of macrophage CD40 in inflammation and immunity and disentangle how its activation affects atherosclerosis. I will finally test the feasibility of targeting macrophage CD40-signaling as a treatment for CVD.
These studies will define the role of CD40-signaling in the innate immune system in health and (cardiovascular) disease. As components of macrophage CD40-signaling have the potential to be amenable to pharmacological manipulation, we will establish their feasibility as novel targets for (CVD) treatment.

SummaryChina s economy has expanded at breakneck speed to become the 3rd largest trading country in the world and the largest recipient of foreign direct investment (FDI). Entry into the WTO in 2001 was a landmark event in this ongoing process and I propose to study several channels through which it spurred China s industrial development. Crucially, I will take an integrated view of the different ways in which Chinese and Western firms interact: through trade flows, as suppliers or competitors, FDI, or knowledge transfers. First, I investigate the existence and magnitude of a causal link from the trade reforms to productivity growth. Second, I look for evidence of capability upgrading, such as increased production efficiency, an ability to produce higher quality products, or introduce new products by innovating. Third, I study the mechanisms for the impact of trade and FDI on local firms, in particular assessing the relative importance of increased market competition and the transfer of know-how from foreign firms. For this analysis, I draw heavily on a unique data set. Information on the universe of Chinese manufacturing firms is being linked to the universe of Chinese trade transactions. These are unique research tools on their own, but as a linked data set, the only comparable one in the world is for the U.S. economy. The Chinese data has the advantage to contain detailed information on FDI, distinguishes between ordinary and processing trade, and contains information on innovation, such as R&amp;D and sales of new goods. Answering the above questions is important for other developing countries wanting to learn from China s experience and for Western firms assessing how quickly Chinese firms will become viable suppliers of sophisticated inputs or direct competitors. By estimating models that are explicitly derived from new theories, I advance the literature at the interaction of international and development economics, industrial organization, economic geography.

China s economy has expanded at breakneck speed to become the 3rd largest trading country in the world and the largest recipient of foreign direct investment (FDI). Entry into the WTO in 2001 was a landmark event in this ongoing process and I propose to study several channels through which it spurred China s industrial development. Crucially, I will take an integrated view of the different ways in which Chinese and Western firms interact: through trade flows, as suppliers or competitors, FDI, or knowledge transfers. First, I investigate the existence and magnitude of a causal link from the trade reforms to productivity growth. Second, I look for evidence of capability upgrading, such as increased production efficiency, an ability to produce higher quality products, or introduce new products by innovating. Third, I study the mechanisms for the impact of trade and FDI on local firms, in particular assessing the relative importance of increased market competition and the transfer of know-how from foreign firms. For this analysis, I draw heavily on a unique data set. Information on the universe of Chinese manufacturing firms is being linked to the universe of Chinese trade transactions. These are unique research tools on their own, but as a linked data set, the only comparable one in the world is for the U.S. economy. The Chinese data has the advantage to contain detailed information on FDI, distinguishes between ordinary and processing trade, and contains information on innovation, such as R&amp;D and sales of new goods. Answering the above questions is important for other developing countries wanting to learn from China s experience and for Western firms assessing how quickly Chinese firms will become viable suppliers of sophisticated inputs or direct competitors. By estimating models that are explicitly derived from new theories, I advance the literature at the interaction of international and development economics, industrial organization, economic geography.

Max ERC Funding

944 940 €

Duration

Start date: 2010-02-01, End date: 2016-01-31

Project acronymMADEM

ProjectMarket Design and the Evolution of Markets

Researcher (PI)Estelle Cantillon

Host Institution (HI)UNIVERSITE LIBRE DE BRUXELLES

Call DetailsStarting Grant (StG), SH1, ERC-2007-StG

SummaryThe broad aim of this research program is to understand how markets get created, how they evolve, and how specific market organizations affect economic outcomes. It combines theoretical and empirical analyses of specific markets and includes the development of new methods to map theory to data and vice versa. Each market provides a concrete ground to explore the broad questions the project addresses and motivates a distinct set of questions. The first class of markets the research will consider are financial markets. These can be viewed as the archetype of large markets where prices play the main role in the allocation. The focus there will on market creation, market evolution and the process of competition. The second class of markets the research will consider are allocation mechanisms where prices do not play a role in the allocation, making efficiency hard to obtain. The focus there will be on strategic manipulation of preferences by participants, their consequences on outcomes and possible remedies. Together, these markets will contribute to our understanding of how market rules affect outcomes and performance, to what extent laissez-faire evolution fosters efficient market organizations, and when and how public intervention can help generate better market organizations.

The broad aim of this research program is to understand how markets get created, how they evolve, and how specific market organizations affect economic outcomes. It combines theoretical and empirical analyses of specific markets and includes the development of new methods to map theory to data and vice versa. Each market provides a concrete ground to explore the broad questions the project addresses and motivates a distinct set of questions. The first class of markets the research will consider are financial markets. These can be viewed as the archetype of large markets where prices play the main role in the allocation. The focus there will on market creation, market evolution and the process of competition. The second class of markets the research will consider are allocation mechanisms where prices do not play a role in the allocation, making efficiency hard to obtain. The focus there will be on strategic manipulation of preferences by participants, their consequences on outcomes and possible remedies. Together, these markets will contribute to our understanding of how market rules affect outcomes and performance, to what extent laissez-faire evolution fosters efficient market organizations, and when and how public intervention can help generate better market organizations.

Max ERC Funding

840 000 €

Duration

Start date: 2008-09-01, End date: 2014-02-28

Project acronymMORPHOSTASIS

ProjectMorphostasis of the intestinal mucosa and it's deregulation in cancer and inflammation

SummaryStem cells at the base of the intestinal crypts are in a dynamic equilibrium with their differentiated derivatives. Homeostatic equilibria depend on the presence of negative feedback loops. The role of the Wnt signaling pathway as a driver of epithelial stem cell self renewal and proliferation in the intestine has been relatively well characterized. Much less is known about the negative feedback signals that must exist to control stem cell behavior and the way these may be deregulated in disease. We found that Indian hedgehog is secreted by differentiated intestinal epithelial cells and acts as a negative feedback signal. Hedgehog signaling acts as a break on Wnt signaling in intestinal precursor cells via a secondary signal in the mesenchyme. We will use conditional mutant mice, our large biobank of patient materials and in vitro experiments to further characterize the signals involved in this feedback loop. Our objective is to study the role of this epithelial mesenchymal signaling circuit in the normal intestine and examine the way it is deregulated in intestinal cancer development and inflammation.

Stem cells at the base of the intestinal crypts are in a dynamic equilibrium with their differentiated derivatives. Homeostatic equilibria depend on the presence of negative feedback loops. The role of the Wnt signaling pathway as a driver of epithelial stem cell self renewal and proliferation in the intestine has been relatively well characterized. Much less is known about the negative feedback signals that must exist to control stem cell behavior and the way these may be deregulated in disease. We found that Indian hedgehog is secreted by differentiated intestinal epithelial cells and acts as a negative feedback signal. Hedgehog signaling acts as a break on Wnt signaling in intestinal precursor cells via a secondary signal in the mesenchyme. We will use conditional mutant mice, our large biobank of patient materials and in vitro experiments to further characterize the signals involved in this feedback loop. Our objective is to study the role of this epithelial mesenchymal signaling circuit in the normal intestine and examine the way it is deregulated in intestinal cancer development and inflammation.

SummaryOver 380 million people suffer from diabetes worldwide, with majority of cases being attributed to type 2 diabetes (T2D). Obesity is a major risk factor predisposing to the development of this disease. T2D is characterized by peripheral insulin resistance in combination with relative insulin deficiency that results in hyperglycemia and hyperlipidemia. Liver and adipose tissue are central for regulation of glucose and lipids levels. However, during T2D the hepatic glucose uptake is reduced while rates of gluconeogenesis and lipogenesis are increased. In the adipose tissue, T2D leads to decreased glucose uptake, perturbations in secretion of adipokines and increased lipolysis. Importantly, dysfunction of the liver and the adipose tissue during T2D is caused by defective phosphorylation signaling cascades and normalization of these pathways was shown to attenuate the course of T2D. However, the specific roles of different classes of signaling molecules in these organs remain poorly characterized. We hypothesize that the cross-talk of different classes of signaling molecules determines regulation of metabolism.
Thus, we aim to identify the signaling networks regulating metabolism. The results generated in my own laboratory suggest that the Pkd family kinases are the crucial regulators of metabolic homeostasis. Specifically, Pkd1 and Pkd2 promote obesity and diabetes while Pkd3 controls liver function. Thus, we plan to characterize the molecular mechanisms controlling Pkds signaling. In parallel, we will utilize screening approaches to identify novel, non-canonical signaling modules (phosphatases and components of the ubiquitin system) regulating abundance, localization and phosphorylation of targets of Pkds and, in the long term, also other kinases implicated in T2D.
By identifying and characterizing the essential signaling networks in liver and adipose tissue the project will contribute to more targeted pharmacological strategies for the treatment of T2D.

Over 380 million people suffer from diabetes worldwide, with majority of cases being attributed to type 2 diabetes (T2D). Obesity is a major risk factor predisposing to the development of this disease. T2D is characterized by peripheral insulin resistance in combination with relative insulin deficiency that results in hyperglycemia and hyperlipidemia. Liver and adipose tissue are central for regulation of glucose and lipids levels. However, during T2D the hepatic glucose uptake is reduced while rates of gluconeogenesis and lipogenesis are increased. In the adipose tissue, T2D leads to decreased glucose uptake, perturbations in secretion of adipokines and increased lipolysis. Importantly, dysfunction of the liver and the adipose tissue during T2D is caused by defective phosphorylation signaling cascades and normalization of these pathways was shown to attenuate the course of T2D. However, the specific roles of different classes of signaling molecules in these organs remain poorly characterized. We hypothesize that the cross-talk of different classes of signaling molecules determines regulation of metabolism.
Thus, we aim to identify the signaling networks regulating metabolism. The results generated in my own laboratory suggest that the Pkd family kinases are the crucial regulators of metabolic homeostasis. Specifically, Pkd1 and Pkd2 promote obesity and diabetes while Pkd3 controls liver function. Thus, we plan to characterize the molecular mechanisms controlling Pkds signaling. In parallel, we will utilize screening approaches to identify novel, non-canonical signaling modules (phosphatases and components of the ubiquitin system) regulating abundance, localization and phosphorylation of targets of Pkds and, in the long term, also other kinases implicated in T2D.
By identifying and characterizing the essential signaling networks in liver and adipose tissue the project will contribute to more targeted pharmacological strategies for the treatment of T2D.

Max ERC Funding

1 499 128 €

Duration

Start date: 2016-06-01, End date: 2021-05-31

Project acronymTENSION

ProjectTargeting replication stress recovery pathways in oncology

Researcher (PI)Marcel van vugt

Host Institution (HI)ACADEMISCH ZIEKENHUIS GRONINGEN

Call DetailsConsolidator Grant (CoG), LS4, ERC-2015-CoG

SummaryGenomic instability characterizes tumors, which have no clear ‘oncogenic-driver’ mutation, including triple-negative breast cancers (TNBCs). These patients do not benefit from molecularly targeted treatment and urgently need better treatment options. Increasing evidence points to replication stress as the driver of genomic instability. Since replication stress compromises cell viability, cells have evolved mechanisms to mitigate this threat.
Recently, I discovered a novel cellular mechanism—mitotic Replication Stress Recovery (RSR)—that acts as an ‘emergency brake’ during mitosis, allowing recovery from high levels of replication stress. This machinery is critical for tumor cell survival, and therefore constitutes a promising target for anti-cancer drug development. However, it is unclear how this mitotic RSR is organized molecularly and how it can be targeted therapeutically.
In this project, I aim to molecularly define and therapeutically target the Mitotic Replication Stress Recovery (RSR) machinery in triple-negative breast cancer cells.
To this end, I will implement a series of complementary innovative strategies. First, I will use mass-spec-based proteomics to molecularly characterize components and wiring of the mitotic RSR machinery. Second, to identify the genetic profiles of cancer subgroups that are sensitive to inactivation of the mitotic RSR, functional genetic screens will be combined with visualization and quantification of replication stress in genomically-defined human cancer samples. Finally, my findings will be translated to the pre-clinical situation by exploring the feasibility of therapeutic inactivation of the RSR machinery in vitro and in vivo in a panel of triple-negative breast cancer models.
In summary, TENSION will provide advanced insight into the composition and wiring of the mitotic RSR machinery and will reveal the potency of targeting this pathway therapeutically for TNBCs and other hard-to-treat, genomically instable cancers.

Genomic instability characterizes tumors, which have no clear ‘oncogenic-driver’ mutation, including triple-negative breast cancers (TNBCs). These patients do not benefit from molecularly targeted treatment and urgently need better treatment options. Increasing evidence points to replication stress as the driver of genomic instability. Since replication stress compromises cell viability, cells have evolved mechanisms to mitigate this threat.
Recently, I discovered a novel cellular mechanism—mitotic Replication Stress Recovery (RSR)—that acts as an ‘emergency brake’ during mitosis, allowing recovery from high levels of replication stress. This machinery is critical for tumor cell survival, and therefore constitutes a promising target for anti-cancer drug development. However, it is unclear how this mitotic RSR is organized molecularly and how it can be targeted therapeutically.
In this project, I aim to molecularly define and therapeutically target the Mitotic Replication Stress Recovery (RSR) machinery in triple-negative breast cancer cells.
To this end, I will implement a series of complementary innovative strategies. First, I will use mass-spec-based proteomics to molecularly characterize components and wiring of the mitotic RSR machinery. Second, to identify the genetic profiles of cancer subgroups that are sensitive to inactivation of the mitotic RSR, functional genetic screens will be combined with visualization and quantification of replication stress in genomically-defined human cancer samples. Finally, my findings will be translated to the pre-clinical situation by exploring the feasibility of therapeutic inactivation of the RSR machinery in vitro and in vivo in a panel of triple-negative breast cancer models.
In summary, TENSION will provide advanced insight into the composition and wiring of the mitotic RSR machinery and will reveal the potency of targeting this pathway therapeutically for TNBCs and other hard-to-treat, genomically instable cancers.

Max ERC Funding

1 972 500 €

Duration

Start date: 2016-08-01, End date: 2021-07-31

Project acronymTUMETABO

ProjectGlycolytic contribution to cancer growth and metastasis

Researcher (PI)Pierre Sonveaux

Host Institution (HI)UNIVERSITE CATHOLIQUE DE LOUVAIN

Call DetailsStarting Grant (StG), LS4, ERC-2009-StG

SummaryCancer lethality is most often associated to occurrence of distant metastases. To grow and become aggressive, cancers may undergo 2 critical adaptations: the glycolytic switch, corresponding to uncoupling glycolysis from the tricarboxylic acid (TCA) cycle, and the angiogenic switch, promoting neovascularization. In this high risk/high gain research program, we propose that the glycolytic switch precedes and promotes angiogenesis and metastatic dissemination in most types of cancer. We further envision that lactate, the end product of glycolysis, interfaces glycolysis and the latter processes through activation of hypoxia-inducible factor HIF-1. A thorough characterization of the molecular pathway(s) initiated by lactate (using transcriptomic, gene silencing, enzymatic and pharmacological interventions) has the potential to unravel new therapeutic targets that would simultaneously inhibit the consequences of the glycolytic switch on cancer aggressiveness. We anticipate the plasma membrane lactate transporters of the (sodium) monocarboxylate transporter (S)MCT family to be key determinants of autocrine and paracrine lactate signaling in cancer. Modulation of their activity or expression (notably by the generation of (S)MCT knock out mice) could thus profoundly affect tumor angiogenesis and metastasis. Since hypoxia is a hallmark of cancer and glycolysis its direct consequence in cancer cells surviving to hypoxia, the findings could have important consequences for the treatment of virtually all types of cancers. It could also impact our understanding of other pathologies, such as wound healing and heart infarction, in which the interplay between glycolysis, HIF-1 activation and angiogenesis could play a critical role.

Cancer lethality is most often associated to occurrence of distant metastases. To grow and become aggressive, cancers may undergo 2 critical adaptations: the glycolytic switch, corresponding to uncoupling glycolysis from the tricarboxylic acid (TCA) cycle, and the angiogenic switch, promoting neovascularization. In this high risk/high gain research program, we propose that the glycolytic switch precedes and promotes angiogenesis and metastatic dissemination in most types of cancer. We further envision that lactate, the end product of glycolysis, interfaces glycolysis and the latter processes through activation of hypoxia-inducible factor HIF-1. A thorough characterization of the molecular pathway(s) initiated by lactate (using transcriptomic, gene silencing, enzymatic and pharmacological interventions) has the potential to unravel new therapeutic targets that would simultaneously inhibit the consequences of the glycolytic switch on cancer aggressiveness. We anticipate the plasma membrane lactate transporters of the (sodium) monocarboxylate transporter (S)MCT family to be key determinants of autocrine and paracrine lactate signaling in cancer. Modulation of their activity or expression (notably by the generation of (S)MCT knock out mice) could thus profoundly affect tumor angiogenesis and metastasis. Since hypoxia is a hallmark of cancer and glycolysis its direct consequence in cancer cells surviving to hypoxia, the findings could have important consequences for the treatment of virtually all types of cancers. It could also impact our understanding of other pathologies, such as wound healing and heart infarction, in which the interplay between glycolysis, HIF-1 activation and angiogenesis could play a critical role.